Abstract Project description: With the growing rate of Alzheimer's disease (AD) and nominal medication effects comes the need for novel treatment approaches. Transcranial direct current stimulation (tDCS) is a method of non- invasive brain stimulation that uses low intensity electric currents to alter the excitability of the brain. Initial evidence suggests that tDCS may improve cognitive functioning in patients with mild cognitive impairment (MCI) and Alzheimer's dementia. The current study directly addresses three key knowledge gaps about the fundamental preconditions for tDCS use: 1) Who benefits, 2) how much electrical current is needed and, 3) how long is treatment needed? This competitive revision of a recently funded R01 (R01AG058724) extends enrollment from only those with MCI to now also include those with early stage dementia of the Alzheimer's type (DAT). This extension embraces the clinical spectrum and avoids the arbitrary and difficult distinction between ?late MCI? and ?early DAT? while concurrently testing this promising treatment approach in those who need it most (i.e., DAT). The study randomizes participants to receive five consecutive daily sessions of HD- tDCS at either sham, 1 milliamp (mA), 2mA, or 3mA ? using neurophysiological change (functional magnetic resonance imaging - fMRI) as the primary outcome measure. Importantly, stimulation targets the lateral temporal cortex; a neuroanatomical target affected early in the course of AD that is also part of the dysfunctional default mode network. This approach provides evidence of target engagement and will be used to optimize the amount (i.e., electrical current intensity necessary to evidence neurophysiologic change). The proposed revision directly addresses a second aspect of ?dose? by providing 25 additional stimulation sessions (30 total), in order to answer the question of ?for how long? stimulation is needed. Participants will complete weekly neuropsychological testing in order to establish dose-response curves and identify optimal treatment parameters (e.g., plateaus suggesting a sufficient dose has been achieved). fMRI will be repeated after the final session in order to evaluate the neurophysiological effects of this extended ?dose? of HD-tDCS. Finally, this is the first tDCS study to integrate the amyloid, tau, neurodegeneration (A/T/N) framework, specifically by using positron emission tomography (PET) ligands to measure beta-amyloid and neurofibrillary tau as well as MRI to quantify brain volume. This approach builds on decades of efforts to enhance in vivo detection of AD pathology by translating this knowledge into a targeted treatment approach. This study immediately addresses field-relevant questions about dose-response (e.g., linear vs. non-linear effects) and mechanisms of action. The results will streamline participant selection in subsequent trials, thereby enhancing treatment outcome and reducing study costs through a precision medicine approach. Taken together, the results will guide the rational prescription of HD-tDCS and serve as the foundation for a novel class of non-pharmacologic treatment.